Identification

Generic Name
Plicamycin
DrugBank Accession Number
DB06810
Background

Plicamycin is an antineoplastic antibiotic produced by Streptomyces plicatus. It has been used in the treatment of testicular cancer, Paget's disease of bone, and, rarely, the management of hypercalcemia. The manufacturer discontinued plicamycin in 2000.

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
Thumb
Weight
Average: 1085.1454
Monoisotopic: 1084.47265336
Chemical Formula
C52H76O24
Synonyms
  • Aureolic acid
  • Mithramycin
  • Mithramycine
  • Mithramycinum
  • Plicamicina
  • Plicamycin
  • Plicamycine
  • Plicamycinum
External IDs
  • A-2371
  • ANTIBIOTIC LA-7017
  • LA-7017
  • NSC-24559
  • PA-144

Pharmacology

Indication

For the treatment of testicular cancer, as well as hypercalcemia and hypercalciuria associated with a variety of advanced forms of cancer.

Pharmacology
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Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Plicamycin is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Plicamycin has shown significant anti-tumor activity against experimental leukemia in mice when administered intraperitoneally.

Mechanism of action

Plicamycin is presumed to inhibit cellular and enzymic RNA synthesis by forming a complex with DNA. Plicamycin may also lower calcium serum levels by inhibiting the effect of parathyroid hormone upon osteoclasts or by blocking the hypercalcemic action of pharmacologic doses of vitamin D.

TargetActionsOrganism
ADNA
antagonist
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

There is no evidence of protein binding, nor is there any evidence of metabolism of the carbohydrate moiety of the drug to carbon dioxide and water with loss through respiration.

Metabolism
Not Available
Route of elimination

Radioautography studies with 3H-labeled plicamycin in mice show that the greatest concentrations of the isotope are in the Kupffer cells of the liver and cells of the renal tubules. Plicamycin is rapidly cleared from the blood within the first 2 hours and excretion is also rapid. 67% percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection.

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

The most important form of toxicity associated with the use of plicamycin consists of a dose-related bleeding syndrome which usually begins with an episode of epistaxis. Plicamycin crosses the blood-brain barrier; the concentration found in brain tissue is low but it persists longer than in other tissues.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Plicamycin.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Plicamycin.
MargetuximabThe risk or severity of cardiotoxicity can be increased when Margetuximab is combined with Plicamycin.
Methoxy polyethylene glycol-epoetin betaThe risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Plicamycin.
PeginesatideThe risk or severity of Thrombosis can be increased when Peginesatide is combined with Plicamycin.
TrastuzumabThe risk or severity of cardiotoxicity can be increased when Trastuzumab is combined with Plicamycin.
Interactions
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Food Interactions
Not Available

Products

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International/Other Brands
Mithracin (Pfizer)

Categories

ATC Codes
L01DC02 — Plicamycin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as oligosaccharides. These are carbohydrates made up of 3 to 10 monosaccharide units linked to each other through glycosidic bonds.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Oligosaccharides
Alternative Parents
Anthracenes / Naphthols and derivatives / O-glycosyl compounds / Tetralins / Aryl alkyl ketones / 1-hydroxy-4-unsubstituted benzenoids / Oxanes / Beta-hydroxy ketones / Acyloins / Vinylogous acids
show 8 more
Substituents
1-hydroxy-4-unsubstituted benzenoid / 1-naphthol / Acetal / Acyloin / Alcohol / Alpha-hydroxy ketone / Anthracene / Aromatic heteropolycyclic compound / Aryl alkyl ketone / Aryl ketone
show 18 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
anthracycline antibiotic, carbohydrate-containing antibiotic, aureolic acid (CHEBI:31856)
Affected organisms
Not Available

Chemical Identifiers

UNII
NIJ123W41V
CAS number
18378-89-7
InChI Key
CFCUWKMKBJTWLW-BKHRDMLASA-N
InChI
InChI=1S/C52H76O24/c1-18-29(72-34-14-30(43(58)21(4)68-34)73-33-13-28(54)42(57)20(3)67-33)12-26-10-25-11-27(49(66-9)48(63)41(56)19(2)53)50(47(62)39(25)46(61)38(26)40(18)55)76-36-16-31(44(59)23(6)70-36)74-35-15-32(45(60)22(5)69-35)75-37-17-52(8,65)51(64)24(7)71-37/h10,12,19-24,27-28,30-37,41-45,49-51,53-61,64-65H,11,13-17H2,1-9H3/t19-,20-,21-,22-,23-,24-,27+,28-,30-,31-,32-,33+,34+,35+,36+,37+,41+,42-,43-,44-,45+,49+,50+,51-,52+/m1/s1
IUPAC Name
(2S,3S)-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-2-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4-{[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-6-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-8,9-dihydroxy-7-methyl-1,2,3,4-tetrahydroanthracen-1-one
SMILES
CO[C@@H]([C@@H]1CC2=CC3=CC(O[C@H]4C[C@@H](O[C@H]5C[C@@H](O)[C@H](O)[C@@H](C)O5)[C@H](O)[C@@H](C)O4)=C(C)C(O)=C3C(O)=C2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@H]2C[C@@H](O[C@H]3C[C@](C)(O)[C@H](O)[C@@H](C)O3)[C@@H](O)[C@@H](C)O2)[C@H](O)[C@@H](C)O1)C(=O)[C@@H](O)[C@@H](C)O

References

Synthesis Reference

Jurgen Rohr, Lily Remsing, Mohammad Nur-e-Alam, Jose Salas, Carmen Mendez, Alfredo Brana, Ana Gonzalez, "Derivatives of mithramycin and methods of making and uses thereof." U.S. Patent US20050192432, issued September 01, 2005.

US20050192432
General References
  1. Wohlert SE, Kunzel E, Machinek R, Mendez C, Salas JA, Rohr J: The structure of mithramycin reinvestigated. J Nat Prod. 1999 Jan;62(1):119-21. [Article]
Human Metabolome Database
HMDB0015682
KEGG Drug
D00468
KEGG Compound
C12389
PubChem Compound
163659
PubChem Substance
99443298
ChemSpider
143544
RxNav
6995
ChEBI
31856
ChEMBL
CHEMBL1237054
PharmGKB
PA165958411
PDBe Ligand
QWP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Plicamycin
PDB Entries
6vgg

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2TerminatedTreatmentBreast Cancer / Esophageal Neoplasms Malignant / Lung Cancers / Mesotheliomas / Neoplasms, Gastrointestinal1
1, 2TerminatedTreatmentEwing's Sarcoma / Sarcomas1
1, 2TerminatedTreatmentMesotheliomas / Neoplasms, Esophageal / Neoplasms, Germ Cell and Embryonal / Neoplasms, Lung / Thymus Neoplasms1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)181.5 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility1.3 mg/mLALOGPS
logP-0.23ALOGPS
logP2.07ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)8.49ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count24ChemAxon
Hydrogen Donor Count11ChemAxon
Polar Surface Area358.2 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity257.01 m3·mol-1ChemAxon
Polarizability114.41 Å3ChemAxon
Number of Rings8ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.6522
Blood Brain Barrier-0.7202
Caco-2 permeable-0.7222
P-glycoprotein substrateSubstrate0.8084
P-glycoprotein inhibitor INon-inhibitor0.7246
P-glycoprotein inhibitor IINon-inhibitor0.7979
Renal organic cation transporterNon-inhibitor0.9474
CYP450 2C9 substrateNon-substrate0.829
CYP450 2D6 substrateNon-substrate0.8772
CYP450 3A4 substrateSubstrate0.6129
CYP450 1A2 substrateNon-inhibitor0.6673
CYP450 2C9 inhibitorNon-inhibitor0.9692
CYP450 2D6 inhibitorNon-inhibitor0.9228
CYP450 2C19 inhibitorNon-inhibitor0.9555
CYP450 3A4 inhibitorNon-inhibitor0.8839
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9814
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9528
BiodegradationNot ready biodegradable0.9779
Rat acute toxicity3.0601 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9888
hERG inhibition (predictor II)Non-inhibitor0.8029
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Fox KR, Howarth NR: Investigations into the sequence-selective binding of mithramycin and related ligands to DNA. Nucleic Acids Res. 1985 Dec 20;13(24):8695-714. [Article]
  2. Lombo F, Menendez N, Salas JA, Mendez C: The aureolic acid family of antitumor compounds: structure, mode of action, biosynthesis, and novel derivatives. Appl Microbiol Biotechnol. 2006 Nov;73(1):1-14. Epub 2006 Sep 30. [Article]
  3. Hampshire AJ, Fox KR: The effects of local DNA sequence on the interaction of ligands with their preferred binding sites. Biochimie. 2008 Jul;90(7):988-98. doi: 10.1016/j.biochi.2008.01.001. Epub 2008 Jan 11. [Article]

Drug created at September 14, 2010 16:21 / Updated at February 21, 2021 18:52